FDA on Monday announced that it was looking to withdraw approval for the low-blood-pressure treatment midodrine hydrochloride because the companies manufacturing the drug failed to provide data from post-approval studies.

The kicker: The drug was approved 14 years ago.

FDA gave midodrine hydrochloride—branded by Shire as ProAmatine and produced by a half-dozen generics firms—the green light in 1996 as part of the fast-track approval program designed to speed to market drugs for diseases with no current treatments.

The catch is that FDA requires post-market clinical trials to ensure that the drug is meeting risk/benefit endpoints. In other words, the regulatory body wanted to make sure no hiccups occurred with the treatment when it hit the general population.

In response, Shire—who acquired the drug when it bought Roberts Pharma in 1999—chose to withdraw the drug as of September 30. The drug firm made it clear that the withdrawal had nothing to do with any safety concerns. In addition, Shire stated that it had conducted post-market trials in conjunction with Roberts, but FDA felt the results were “inconclusive.”

According to a release by FDA, none of the companies selling the drug have provided any data to prove that the treatment is beneficial. That said, some 100,000 people were treated with the midodrine hydrochloride last year alone.

“We’ve worked continuously with the drug companies to obtain additional data showing the drug’s clinical benefits to patients,” stated Norman Stockbridge, director of the Division of Cardiovascular and Renal Drugs in the FDA’s Center for Drug Evaluation and Research. “Since the companies have not been able to provide evidence to confirm the drug’s benefit, the FDA is pursuing a withdrawal of the product.”

FDA stated that patients currently on midodrine hydrochloride should not stop taking the medication. Shire now has 15 days to respond to FDA’s inquiry and provide some data supporting the drug. Shire did not respond to calls as of Monday afternoon. In addition, it’s unclear as to why FDA waited so long to ask for more data and whether any adverse reactions have been reported pertaining to the drug.

This is a huge problem for Roche who purchased the treatment as part of its merger with Genentech. The drug firm could see sales drop by $1 billion if FDA agrees with the panel and ceases use of the drug for breast cancer. The drug earned Roche $5.7 billion in 2009.

“We are disappointed by the committee’s recommendation and believe Avastin should continue to be an option for women with this incurable disease,” stated Sandra Horning, Roche’s global head of clinical development hematology/oncology, in a release. “We will continue to discuss the data from the more than 2,400 women who participated in three Phase III studies with the FDA. This recommendation does not impact Avastin’s approved uses for other cancer types.”

Avastin (in combination with chemotherapy) was given fast-track approval in early 2008, because it treated HER2 negative breast cancer, a form of the disease with few treatment options. FDA requested that Genetech release the results of two post-market trials to determine how effective the drug is at improving patient lifespan.

According to the two trials, the treatment only slowed cancer progression by approximately a month and didn’t do anything to boost patient survival. Additionally, patients taking Avastin had more adverse reactions than patients taking chemotherapy alone.

FDA will give a final ruling on Sept. 17.

Of course, reading the tea leaves in FDA’s cup is often an exercise in futility. Determined to make as few waves as possible, FDA officials have perfected the art of “split-the-difference” decision-making. But Hamburg and Sharfstein are reputedly a different breed of leader. And given the longstanding guerilla war between FDA’s safety officials and its drug reviewers, the outcome of Avandia’s trial may signal a possible shakeup inside the agency itself.

But portents aside, will justice be done in the case of GSK’s once-heralded, now much-maligned diabetes drug?

Imagine the process as a courtroom drama. At the prosecution’s table sit two familiar doctors: David Graham, the outspoken FDA drug safety expert; and Steve Nissen, the equally outspoken chairman of cardiology at the Cleveland Clinic. Both made their names a decade ago leading the charge against Vioxx, and the Avandia dustup has further burnished their reputations as anti-pharma crusaders. Both advocate Avandia’s withdrawal and have published studies making that case to the FDA advisory panel.

Graham’s study, published June 28 by the Journal of the American Medical Association (JAMA), is based on a retroactive analysis of the 1999–2009 records of 227,571 Medicare patients on Avandia or its same-class competitor, Takeda’s Actos. The report finds that Avandia was associated with a higher risk of stroke, heart failure (but not heart attack), and death, and concludes that more than 47,000 people could have escaped these health emergencies had they been on Actos rather than Avandia. Graham has long maintained that Avandia remains on the market only because FDA reviewers are defending their original decision to approve it.

Nissen’s study, published June 28 by the Archives of Internal Medicine, updated his 2007 meta-analysis, using a database of 56 trials including 35,531 patients. He found that Avandia raised the heart attack risk by 39 percent, compared to placebo; however, the rate of mortality was not elevated. Nissen attributes the differences between his data and Graham’s to the fact that his cohort’s average age was 54, while Graham’s was 74. “It is really impossible to argue that this drug has benefits that exceed its hazard,” Nissen told The New York Times.

Additional evidence includes a February 2010 bipartisan Senate investigation into 250,000 internal GSK documents. The most serious findings charge that GSK knew about the increased cardiovascular risks for two years, and FDA for about half as long, without alerting the public.

At the defense table sit a row of lawyers flanked by PR flaks, with a few slightly rumpled scientists sprinkled in for effect. “Results from six controlled clinical trials have been reported since … FDA last reviewed questions about the cardiovascular safety of Avandia in 2007. Taken together, these trials show that it does not increase the overall risk of heart attack, stroke, or death,” the suits intone as one.

The most recent study, presented on June 28 at the annual meeting of the American Diabetes Association (ADA), was designed to test how best to treat patients with both diabetes and coronary artery disease. In this 2,400-patient observational study, Avandia was not prescribed randomly but by the individual doctor’s discretion: Some patients got medication alone, others medication plus angioplasty or bypass surgery. At 4.5 years of follow-up, the rates of heart attack, stroke, or death were slightly less for those on Avandia (or Actos) than metformin.

As for the Senate’s accusations about concealing known dangers from the public, GSK denies all such charges. It also insists that the two new studies critical of Avandia, as retrospective analyses, are open to interpretation. Citing opposition by doctors—including ADA and American Heart Association officials—to any move to yank Avandia, GSK’s legal eagles rest their defense with a rhetorical plea to let science prevail over uncertainty.

The FDA advisory committee will certainly sweat over the mass of Avandia science, but uncertainty is likely to remain. Following FDA’s 2007 decision to allow GSK to keep selling Avandia despite possible dangers, the agency ordered the company to conduct a large, randomized trial comparing Avandia to Actos to determine which is safer. Yet with enrollment flagging, the drug may well be off patent before results are in.

Now that study looks like a waste of time and money. As the JAMA editorial accompanying Graham’s study says, “Converging lines of evidence suggest that Avandia is less safe than Actos, whereas no data suggest that the converse is true. The real question is, given all the accumulating safety concerns about Avandia, why, exactly, a patient might want to receive the drug or why a physician would choose to prescribe it when there is an available and quite possibly safer alternative?”

In other words, it is a question not merely of safety and efficacy but also of value. Commissioner Hamburg may decide to ask GSK to pull Avandia to make precisely that point.

Janet Woodcock

While the convention floor of the 46th annual meeting of the Drug Information Association bustled with the usual vendors touting the latest and greatest clinical trial technology, the panels (particularly those that featured FDA members) had a remarkably somber tone.

The main refrain was: “Things are going to change and everyone must step up or get trampled.” However, those comments were often followed by: “We are going to have to change, but we have no idea how or how much it will cost.”

“Drug development is in crisis, and there is a demand for better evidence,” said Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research during her panel presentation “The Impact of New Comparative Effective Requirements.”

“Right now, we are at the same point with comparative effectiveness as we were with drug efficacy in 1960,” Woodcock said. “We didn’t know how to do it, and there was a lot of resistance to it. There was a battle over efficacy that almost died.

“In 2010 there is no requirement for comparative evaluation pre-market,” Woodcock continued. “Effectiveness is something different. Pre-market  clinical trials won’t give you that effectiveness, because they aren’t done in a ‘real world’ setting. The preferred methodologies we don’t actually know. There are people out there that think we can just push a button on healthcare data sets and get the answers.”

She also noted that pharmaceuticals, unlike other health technologies, have a tremendous evidence base. “The FDA Amendments Act explicitly calls for additional evidence regarding safety when new safety questions come up after marketing,” she said. “Comparative effectiveness is a call for more outcomes data to guide practice. It’s a trajectory that industry must recognize. This is where we are all going together.”

She pointed out that there are budgetary restraints in government so it will fall into pharma’s lap to perform these new pre and post market trials. “Unfortunately, right now, drug development is in crisis, but this isn’t a good time for the pharma industry to take on new requirements,” Woodcock said. “For the regulators, this is a huge problem. Drug regulators are caught between two societal expectations and demands. On one hand you have the rising desire for certainty, and on the other they want innovative drugs.”

In Europe, they think that the tech assessors such as NICE are going to start planning pre-market, during the drug development process, and give advice on how to fulfill the technology assessors requirements. In that way, the drug development process can be seen as a seamless process that takes care of the regulators needs as well as the payer’s needs.

The Tough Questions
“The problem that we have is that we had 50 years of experience working this out,” Woodcock said. “The technology assessors don’t think the same way regulators do—we have a great deal more experience in trial methodology and analysis. We realize the limitations in data and the methodology in CE has not been worked out.”

She said that there will be tremendous pressure on industry and regulators for more evidence and that’s what’s driving the controversy about safety. The question is: Who in the US will generate this initial evidence, and what evidentiary standards will be applied? FDA just opened a study with the Institute of Medicine on the use of observational studies and other types of databases versus randomized control trials to evaluate safety signals.

Woodcock brought up two more questions: How will the standards be implemented and when in the drug development product should what evidence be generated? How much certainty should we have in any given point during drug development?

“It’s imperative that the United States develop a clinical trial infrastructure,” Woodcock said. “We don’t have a machine to generate all this evidence. We don’t have any mechanisms in place to generate all this evidence. It’s time that we develop the capacity to find out these answers in a way that doesn’t cost hundreds of millions of dollars every time we ask a question.”

The Harder Answers
For certain diseases, like cancer, the answers might be driven from the patient side. The Cystic Fibrosis Foundation has set up such a network for their patients so they can get into trials for new treatments rapidly—and so that those new treatments can rapidly be evaluated.

Another suggestion Woodcock offered is to move on the science of new personalized medicine. “That’s the best way to improve the value of medicine,” Woodcock said. “We must target it towards populations that stand to benefit more and don’t have as much risk. We are there on the science.”

Finally, she said that there’s new science of safety evolving and that has to do with Sentinel and the use of electronic health records. That science will help industry and FDA evaluate the performance of medical products once they are released. “The problem is that the science is also in its infancy, and there are a large number of questions that we’ll have to answer before those types of databases can be used to answer the questions we have about outcomes,” Woodcock said. “Comparative outcomes data are essential for evidence-based medical practice, and they have to be gathered in real world settings so in some ways the premarket world is not the time to get this information. Methodologies for doing this kind of research in the US are lacking. Work is ongoing, but more needs to be done, and we need to incorporate new science so we can understand what we are doing.”

The data was released at the annual meeting of American Society of Clinical Oncologists. According to Roche, Genentech’s parent company, patients treated with a combination of Avastin and chemo, followed by the continuation of Avastin alone, survived more that 14 months without seeing symptoms worsen. Comparatively, patients on chemotherapy alone were progression-free for about 10 months.

Roche studied 1,873 untreated patients with advanced ovarian cancer. Patients taking Avastin with chemo saw a higher frequency of adverse events including low white blood cell counts, pain, gastrointestinal problems, and hypertension.

Here’s a run down of the other news coming out of Chicago:

•Argos Therapeutics released positive Phase II data about its AGS-003 drug in combination with sunitnib for the treatment of advanced renal cell carcinoma. “Sunitinib has been shown to modulate the immune system by decreasing T-regulatory cells that can potentially suppress immune responses in the tumor microenvironment,” said Asim Amin, co-director, Immunotherapy Program for the Blumenthal Cancer Center.

•Novartis announced that a Phase II trial involving the drug Afinitor showed positive results in dropping the size of benign brain tumors caused by tuberous sclerosis. Of the 28 patients in the study, 75 percent saw a decrease of around 30 percent in size.

While Merck’s net profits might be a little low in the wake of the Schering-Plough merger, it’s pipeline—and future sales—are far from bleak.

According to a new report from analyst firm Deutsche Bank, Merck has no less than 18 drugs in Phase III development, with three slated for launch within the next year and a half. Another 25 therapies are in Phase II trials—a good chunk of which are “innovative therapies for unmet needs.”

The three drugs analysts are keeping a close eye on are: boceprevir, vorapaxar (TRA), and sugammadex. Here’s a little bit of info from the report on each of the treatments to get readers up to speed.

• Boceprevir is a protease inhibitor for the treatment of hepatitis C virus is a Schering-Plough drug used for treatment naïve patients. A trial, expected to conclude any day now, is looking for improvement in patients taking the drug in combination with peginterferon/ribavirin as opposed to patients taking that treatment alone.
• Vorapaxar (TRA) is a thrombin receptor (PAR-1) antagonist in development for the prevention and treatment of arterial thrombosis. TRA therapy showed a lot of promise in a large phase 2 study for potentially reducing ischemic events without increasing bleeding risk when combined with agents like Plavix.
• Sugammadex (Bridiron) is a first in class, selective, relaxant binding agent for use in anesthesia that can encapsulate the commonly utilized muscle relaxants rocuronium and vecuronium, reversing and preventing their neuromuscular blocking action.

“Merck’s expanded base business, more diverse product portfolio and agile, increasingly lean cost structure, will support stable earnings per share growth over the next several years,” Deutsche Bank Analyst Barbara Ryan stated in the report. “Further, the Merck/Schering-Plough combined late stage pipeline has the potential to extend this record into the next decade.”

Biotech firm InterMune took an ugly hit on Tuesday as news broke that its lung disease drug Esbriet (pirfenidone) will require additional clinical studies, and won’t be getting the seal of approval from FDA any time soon. The news caused InterMune’s stock to drop a staggering 78 percent, according to Reuters. Analysts have downgraded the stock to values as high as $60 and as low as the mid-teens.

Esbriet is being used in trials to treat patients suffering from idiopathic pulmonary fibrosis (IPF), a debilitating and deadly lung infection that causes inflammation and scarring. People suffering from the disease typically have only two to five years to live and a 20 percent survival rate.

The treatment was involved in two large-scale clinical trials, but the drug failed to meet its endpoints in one. However, the Phase III data that the company collected was expected to be enough to get the green light from FDA.

In a complete response letter to InterMune, FDA requested another clinical trial to further prove the efficacy of Esbriet, beyond the endpoint met in the previous study. There are currently no FDA-approved medications for IPF, and an FDA advisory committee recommended that the treatment be approved back in early March.

Dan Welch, chairman, CEO and president of InterMune, said that he intends to meet with FDA as soon as possible to find out why its committee rejected the drug, and understand how to expedite the approval process. The bad news is that the meeting may not occur for 60 to 90 days.

Welch would not elaborate on the kind of data FDA would like to see, or what type of trial the regulatory body is looking for, nor would he comment on previous discussions with FDA.

FDA Commissioner Margaret Hamburg announced, on Thursday, a new joint initiative between industry, FDA, and non-profit organizations designed to fast-track modern combination treatments for tuberculosis. Where once it took more than two decades to create new therapies for TB, this collaboration is expected to produce working treatments in less than six years, providing much-needed help for people developing nations.

Dubbed the Critical Path to TB Drug Regimens, this program will enable different stakeholders to share new compounds and ideas in an effort to shorten the time it takes to develop new multi-drug therapies. The initiative is spearheaded by the Bill & Melinda Gates Foundation, the Critical Path Institute, and the Global Alliance for TB Drug Development, with partners including members of FDA, the World Health Organization, Johnson & Johnson, Sanofi-Aventis, and Pfizer.

“FDA is absolutely committed to working with industry and other partners to speed access to new, safe, and highly-effective treatments for TB, which continues to mutate and spread,” stated Hamburg in a release. “I’ve seen first-hand the public health impact and personal tragedy of drug-resistant TB. This creative approach mirrors FDA’s own investments in innovative regulatory science that ensures the best new medical technologies—including combination therapies—reach patients as soon as possible.”

According to TB Alliance President and CEO Mel Spigelman, the catalyst for this collaboration was a critical mass of raw materials or substrate in the pharma pipeline.

“The real issue for TB has been that it’s a truly neglected disease, and until not that long ago no one was working on new drugs even though there was a clear need for it,” Spigelman said in an interview with Pharm Exec. “We presented this idea five years ago, but there simply weren’t enough compounds to work with.”

There are now nine compounds in clinical development for TB. This critical path is intended to get one or more new regiments registered and adopted as soon as possible.

What makes TB drug development so complicated is that treating the disease with a single drug almost always leads to treatment resistance (sometimes within as little as two weeks). While patients might feel better in the short term, the disease never really goes away. To completely defeat the TB, patients must be treated with a regimen of multiple drugs or a drug cocktail.

Traditionally, a company looking to add new drugs to a treatment regimen would have to spend a minimum of six years in testing. A Phase III study alone could take four years to show results. A pharma company trying to develop a cocktail of four treatments could feasibly spend up to 25 years testing each drug.

“Whether the combination happens to have one new drug in it or four new drugs, you are really testing that combination once you get beyond two weeks,” Spigelman said.

About two years ago, the TB Alliance began reaching out to different partners for research purposes and to look at combination of different drugs in animal models. The organization formed bilateral agreements with multiple sponsors and brought them into the initiative one by one to work with academic collaborators on testing preclinical combinations.

“We’ve already identified, in mice, at least 10 different regimens that look much better than the standard treatment,” Spigelman said. “That’s a building block that helps forge the pathway in the clinic.”

This type of approach could also be translated to other diseases such as malaria. HIV had a similar critical path in the 1990s, when a number of pharma companies share d  knowledge  as a springboard to get combinations developed more quickly.

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Big Pharma companies touted improved pipelines with more focused and productive R&D and licensing-in of innovative compounds when needed to build confidence with investors. Many gave assurances of the replacement of already lost or impending lost revenues as a result of the blockbuster “patent cliff” between 2008 and 2014. They offered more streamlined organizations, new business models, expansion into emerging markets with promising growth in branded, off patent drugs as well as innovative drugs, and, for some, the growth of their share of the expanding worldwide vaccine market. A few that already had existing lower-margin ancillary businesses, e.g., OTC or animal health, on the ground in emerging markets touted their related investments and increases in revenue. Notably, Martin Mackay, president of global R&D, Pfizer and Elliott Sigal, chief scientific officer and president of R&D, BMS presented rather than their company CEOs.

Some specialty companies had very positive news with respect to revenues and products. An outstanding example was TEVA announcing the achievement of a 16.4 percent share of U.S. Rx’s and number one status while fifth place Pfizer has only 5.6 percent. They shared news of growth of their branded neurological products, e.g., Coxapone (glatiramer acetate) for multiple sclerosis and Azilect (rasagiline)  for Parkinson’s and the anticipated maintenance of the split in their business—70 percent generic, 30 percent brand—continuing into 2015.

David Hung, president and CEO of Medivation, bragged about the cost efficiency of their business model in achieving the Phase III status for Dimebon (latrepirdine) for Alzheimer’s disease within less than 6 years for an investment of only $175 million dollars. He presented an intriguing explanation of the mechanism of action of Dimebon in enhancing mitochondrial function, neuronal survival and neuronal sprouting—all supportive of the positive efficacy data reported for the drug in AD so far. The drug is in Phase III development and partnered with Pfizer.

Big Biotech’s Amgen CEO Kevin Sharer, chairman, CEO and President, was reassuring in giving the reasons he thought “we have a lot to feel good about in 2009”—they streamlined operating expenses, held up well against biosimilars in Europe, advanced their Phase II pipeline and have stable base of business. He shared they were closer to global approvals for Prolia (denosumab) in postmenopausal osteoporosis with the sales team in place. He noted they had 30,000 applicants for the 500 new sales slots for the product.

Doug Braunstein, head of investment banking at JP Morgan in his opening remarks to the conference Monday morning claimed signs of the beginning of a “turn in the economy.” Along with an update of several market indicators, he announced that “the IPO market returned in mid-2009” and provided further encouragement with fact that 50 IPO filings are lined up for 2010.

Later that day, the keynote luncheon speaker, Jamie Dimon, chairman and CEO, JP Morgan Chase & Company focused his remarks on the “extraordinary times” we are facing and the impending reform of financial regulations and health care. He provided his analysis of what went wrong and what needed correction—emphasizing the need for “better regulation”… but “not just more”—as he listed the events of the financial crisis.  He voiced support for a more efficient health care system and expects a bill will be passed.

Tuesday’s luncheon keynote speaker Tom Scully, former administrator of the Center for Medicare and Medicaid Services under George W. Bush and general partner, Welsh Carson Anderson and Stowe, expanded on Dimon’s initial health care reform remarks by giving an in-depth analysis of what he called the “universal coverage bill”—based on current Senate and House versions. His conclusion was that the interests of all the major healthcare industry stakeholders—satisfied in order to get political agreement—fared relatively well. He concluded the “major losers” will be the taxpayers upon whom the cost of the expansion of Medicare to 15–16 million new beneficiaries would fall. He declared acute care hospitals as the “biggest winners.”

In response to a question from a European in the audience who couldn’t understand why a single payer system wasn’t acceptable, Scully stated very strongly that the undertaking was extremely complex and the best that could be expected was an incremental change in the system. He admitted that it was very difficult to draft and pass the 2006 Part D drug legislation even with a heavily Republican dominated House and Senate.

There were 337 healthcare (276 public and 61 private) companies presenting to 1,387 public investors and 1,278 private equity and VC investors with record breaking number of 7,000 one-on-one meetings. Total registered attendees reached 6,500.

Public company presentations were Webcast live and are available on-demand (subject to company consent) for three months after the conference at events.jpmorgan.com.